Nedd8-activating enzyme inhibitor MLN4924 (Pevonedistat), inhibits miR-1303 to suppress human breast cancer cell proliferation via targeting p27Kip1

Exp Cell Res. 2020 Jul 15;392(2):112038. doi: 10.1016/j.yexcr.2020.112038. Epub 2020 May 1.

Abstract

MLN4924/Pevonedistat, a Nedd8-activating enzyme (NAE, E1) inhibitor, has shown notable anti-cancer effect in pre-clinical trials, but it still faces tolerance resistance risk. Combination target therapy indicates a much better clinical effect than single target, and miRNAs are beneficial for easy detection in bodily fluids and tissues. Up to now, MLN4924 and miRNA-targeting combination approaching to treat breast cancer patients remains largely unknown. Here, microRNA-seq analysis showed that the expression of miR-1303 was significantly decreased after MLN4924 treatment in breast cancer cells. Moreover, miR-1303 was abnormally high in breast cancer tissues, and breast cancer patients with high miR-1303 showed poor prognosis. Functionally, excessive miR-1303 promoted the malignant phenotypes of breast cancer cells. Excessive miR-1303 accelerated cell cycle progression by promoting G2/M arrest. Furthermore, we revealed that miR-1303 targeted p27Kip1 to release G2/M arrest. Notably, excessive miR-1303 partially disturbed the anti-cancer effect of MLN4924. These findings provide potential evidences for combined anti-cancer target therapy of breast cancer patients in the future.

Keywords: Breast cancer; Combined drug therapy; MLN4924; miR-1303.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Biomarkers, Tumor
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Cycle
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism*
  • Cyclopentanes / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • MicroRNAs / genetics*
  • NEDD8 Protein / genetics
  • NEDD8 Protein / metabolism*
  • Prognosis
  • Pyrimidines / pharmacology*
  • Survival Rate
  • Tumor Cells, Cultured
  • Ubiquitin-Activating Enzymes / antagonists & inhibitors*
  • Ubiquitin-Activating Enzymes / genetics
  • Ubiquitin-Activating Enzymes / metabolism

Substances

  • Biomarkers, Tumor
  • CDKN1B protein, human
  • Cyclopentanes
  • Enzyme Inhibitors
  • MIRN1303 microRNA, human
  • MicroRNAs
  • NEDD8 Protein
  • NEDD8 protein, human
  • Pyrimidines
  • Cyclin-Dependent Kinase Inhibitor p27
  • Ubiquitin-Activating Enzymes
  • NAE protein, human
  • pevonedistat